Preparation And Study Of A PH-responsive Calcium Carbonate Hybrid Nanosphere Targeted Drug Delivery System

Targeting drug delivery system（TDDS）,attracting much public attention in the cancer treatment,because of slow releasing rate,targeting,stability,shortly side-effects,etc.There are some drawbacks in the current development of drug delivery systems,such as the lack of targeting,expensive raw materials,complex preparation systems and sudden drug release.In order to solve these problems,this study selected calcium carbonate（CaCO₃）,with good biocompatibility and low cost,and carboxymethyl chitosan（CMCS）as a raw material.The folic acid（FA）it was chemically bonded to the surface of polysaccharide macromolecules.FA with tumor targeting was modified to obtain a drug carrier material with tumor targeting properties.Finally,it can increase the drug loading,reduce the toxic side-effects of drugs,and achieve the purpose of targeted drug delivery.Firstly,the coupling of folic acid to CMCS by amidation reaction was studied to obtain the carboxymethyl chitosan coupling folic acid.It was characterized by fourier transform infrared spectroscopy（FT-IR）and X-ray diffraction（XRD）.The results showed that FA was successfully coupled to CMCS,and the coupling degree of FA was 4.7%.Secondly,calcium carbonate was crystallized in FCMC solution to form a FCMC/CaCO₃ hybrid nanospheres by a simple self-assembly method.Meanwhile,the structure of the nanospheres were confirmed by scanning electron microscope（SEM）,thermogravimetric analysis（TGA）,XRD,FT-IR and nitrogen adsorption-desorption analyses.The results show that the FCMC/CaCO₃ hybrid nanospheres have regular spherical shape,and the hybrid spheres are composed of calcite,aragonite and polysaccharide polymers.The hybrid nanospheres have mesoporous structure and supply a potential loading space for anticancer drugs.At the same time,the influence of FCMC/Ca²⁺molar ratio on the morphology of the nanospheres was discussed.The results showed that the spherical aggregates with regular morphology were obtained at FCMC/Ca²⁺molar ratio of 4:1 after 24 h reaction,and the average particle size of the nanospheres was 207 nm.In addition,the drug loading and drug releasing properties of FCMC/CaCO₃ hybrid nanospheres were studied.The hydrophilic drug metformin（MET）and hydrophobic drug methotrexate（MTX）were used as model drugs.The results showed that FCMC/CaCO₃ hybrid nanospheres had high encapsulation efficiency and drug loading for both drugs.When pH value was simulated in normal tissue at pH 7.4,the drug release was very low but the drug release rate of nanospheres was accelerated obviously when pH value was under simulated acidic pH of tumor cells（pH 5.0）.In the simulated acidic pH environment of tumor cells,hybrid nanospheres have good drug release performance depends on their excellent pH sensitivity and controlled release ability.It is expected to be used as an intelligent targeting drug delivery system for the treatment and prevention of cancer.